The present invention relates to a device for delivery of charged drug molecules through the skin, employing an iontophoresis phenomena.
Recently, iontophoresis has gained increased attention as an effective method for topical application of ionic agents or drugs by promoting absorption through skin of a human or animal. Iontophoresis techniques are disclosed in, for example, Glass JM et al., Int. J. Dermatol. 19,519 (1980); Russo, J., A., J. Hosp. Pharm. 37,843 (1980); Gangarosa LP et al., J. Pharmacol. Exp Ther. 212,377 (1980); Hill JM et al., Ann. NY. Acad. Sci. 284,604 (1977).
Iontophoresis has been used for transdermal delivery of charged molecule drugs into the skin. The method employs a dc voltage between two electrodes, attached to the skin, and under one of said electrodes there is provided a layer of the drug to be introduced. The drug is migrated into the skin due to the applied electric field.
Because of impedance of the outer layers of the skin, the drug penetrates the body's interstitial fluids, from which it is diffused into the body.
These electric fields contain a large amount of ions, by which electric current is passed into the body. A main disadvantage found in iontophoresis is the fact that it causes burns and irritation to the skin. This effect can be explained by the high impedance between the two electrodes which results in the development of a very high power converted into heat thusly causing skin burns. In order to eliminate these skin burns the impedance between the two electrodes must be decreased.
In an equivalent circuit to that described above (such as the human membrane) Pilla et al describe in the Journal of Electro Chemical Society 124 (1977) 1697, a circuit containing capacitors and resistors. Thus they concluded that in order to increase migration current, the impedance of the capacitors and resistors should be decreased.
The impedance of a capacitor is inversely proportional to the frequency. Increasing the frequency decreases the impedance of the capacitor and decreases the impedance of the human body.
Experiments showed that applying square wave pulses of 0 volts to 4 volts and a duty cycle of 1:1 at 50-500 kHz, and having a peak current of 50 mA, with an average current of 12 mA, passed through the human body, without causing burns. The foregoing suggest that application of pulses at a current or voltage of various shapes, at high frequency will accomplish the desired objective.
Another way to reduce the body's impedance is to decrease the ohmic resistance. The ohmic resistance between two electrodes depends on the configuration of the electrical cell. In a planar configuration, which consists of two planar parallel electrodes, the resistance depends on the gap between the electrodes. By decreasing the gap the electrical field increases, causing a decrease in resistance.
In a concentric cylinder configuration, most of the ohmic potential drop occurs near the inner cylinder and does not depend solely on the electrode gap. In a circular planar electrode, most of the ohmic potential drop occurs at a region of the same order of magnitude as the radius of the electrode, and is proportional to the radius. By changing the configuration of the electrodes, the ohmic resistance can be changed too, as is shown by J. Newman et al. in Electrochemical Systems, published by Prentice-Hall, Englewood Cliffs, NJ (1973).
There is no convenient way to produce planar or cylindrical configurations, using the human body as the electrical medium. The circular planar electrode is more convenient. However, it was shown by Aoki et al. "Electro Chemical Journal" that thin longitudinal electrodes resemble the behavior of cylinders. This fact also enables use of thin rectangular electrodes.
A strong effect of cell configuration on iR (current x resistance) drop was shown by Bond et al, Electronal Chem. (1984) 257. They were able to take electrochemical measurements of extremely non conductive electrolytes, at temperatures down to the freezing point of the solvent (eutectric mixtures)--solvents such as acetonitrile and acetone--by using small circular electrodes.
At these low temperatures large electrodes cannot be utilized because ohmic resistance is very high.
The electrolyte is non-uniform and may contain even insulating regions. Even though the human body is non-uniform and has high specific resistance, the effect of size and shape of the electrodes influences the resistance between the electrodes.
Other structures and designs of iontophoretic transdermal devices were described in the following patents:
1. United Kingdom Patent GB2104388 describing a light device consisting essentially of two electrodes, a current being conducted between these electrodes through a patient's body, causing an ionized drug to be forced through the skin.
2. U.S. Pat. No. 4,141,359 describes an iontophoresis device, having means for predetermined settings of limits of impedance enabling control of currents, hence control of drug flow.
3. U.S. Pat. No. 4,164,226 describes inhibition of perspiration, although it also maintains general iontophoretic applications. Burns on the skin are eliminated by interposing a relatively thick porous and preferably moistened material between a negative electrode and the skin. Electrodes with separate conductive areas are suggested.
4. U.S. Pat. No. 4,419,092 describes a structure of an electrode for use in electrophoretic devices having a membrane through which ions can migrate into skin, and include an electrode mounted on top of a reservoir connected to an energy source.
5. U.S. Pat. Nos. 4,557,724 and 4,640,689 as its continuation in part describe systems whereby drugs are charged electrically in a reservoir and driven towards the skin into the blood stream by passing a current through the skin between two electrodes which are connected to a power source.
6. U.S. Pat. No. 4,764,164 describes a device for iontophoresis which includes a pulse generator, a working electrode and a counter electrode. The device has means for discharging and charging the charges accumulated in the electrodes during intermission periods between the pulses generated by the pulse generator. The device claims to eliminate the irritation and burns of the skin. The effective operation time of the device is 20% of the total time applied at relatively high currents of 10-30 mA. The major feature of said patent is reduction of skin capacitor impedance by using a high frequency pulse.
The iontophoretic devices disclosed in prior art known to us generally include connecting an output terminal of a continuous direct current generator or pulse generator to a working electrode composed of a metal plate or other conductive substances. These last mentioned electrodes are covered with a gel, or a moistened pad of porous material impregnated with an aqueous solution, including an ionic drug and a counter electrode structured similar to the working electrode but without the drug.
From the foregoing description, is should be clear that the actual application of iontophoresis through these prior art techniques has major disadvantages including but not limited to low efficiency and skin burns. Although iontophoresis is a very effective method for drug application, these disadvantages have limited its widespread use.
By way of explanation, in all of these foregoing iontophoresis approaches the following major problems recur.
1. Because of the high impedance of a human or animal body, an application of electric current causes a larger power to develop which converts into heat with resultant burns and irritation to the skin of the recipient using the device.
2. Electrode designs in devices described in the prior art known to us do not teach specific geometric relations to solve this burn problem by reduction of ohmic resistance of the skin. This inadequacy is overcome by the devices which are the subject of this invention.
Accordingly, it is an object of the present invention to eliminate the above mentioned problems in the prior art by providing an iontophoretic device capable of sufficiently decreasing the skin's total impedance (ohmic resistance and capacitor impedance) thereby allowing an iontophoretic device to be used under a relatively low voltage and a relatively high electric current, also permitting the iontophoretic device to be applied safely to the human or animal skin under a high current without causing irritation, burns and rubefaction of the skin.
Another object of the present invention is to provide an iontophoretic device which is light in weight, easily manufactured and assembled and capable of direct and simple application to a recipient's skin and which can be operated over a long period of time.